Epigenetic regulation of cardiac regeneration after injury.

Información del proyecto

HeartATAC

Identificador del acuerdo de subvención: 751988

DOI

10.3030/751988

Proyecto cerrado

Fecha de la firma de la CE 13 Marzo 2017

Fecha de inicio 1 Julio 2017

Fecha de finalización 30 Junio 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 177 598,80

Aportación de la UE

€ 177 598,80

Coordinado por

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

Periodic Reporting for period 1 - HeartATAC (Epigenetic regulation of cardiac regeneration after injury.)

Período documentado: 2017-07-01 hasta 2019-06-30

Resumen del contexto y de los objetivos generales del proyecto

Cardiovascular disease is a leading cause of morbidity and mortality worldwide, and there is a constant and urgent need for novel, more effective therapies to treat it. At birth, mammalian heart muscle cells still have the ability to regenerate after injury. However, in the first few days after birth, this ability is firmly shut down. Recently, evidence has accumulated that the heart muscle cells in adult mammals, including humans, undergo significant renewal. These new insights challenge the long-held view that the heart muscle cells cannot be renewed during life. Still, adult renewal rates are insufficient to cope with the massive loss of heart muscle cells in cardiac injury, such as myocardial infarction.

The goal of this proposal is to better understand the mechanisms by which the heart switches from a proliferative, pro-regenerative state during development to a quiescent, non-regenerative state in adulthood, to ultimately apply this knowledge to reverse clinical phenotypes after myocardial infarction.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have identified a novel factor, Arid1a, that is normally suppressing heart muscle cell division after birth. We have generated a mouse model in which Arid1a is inactivated in heart muscle cells and obtained novel insights into the mechanisms by which cell renewal is regulated in the heart after birth. Furthermore, we have studied the role of Arid1a in adult hearts after injury. We have established that Arid1a is not required for normal heart function. Moreover, we found that after injury, Arid1a is suppressing cell cycle activity, and thus preventing regeneration of heart muscle cells. Suppression of Arid1a in heart muscle cells after injury was not sufficient to revert the damage or induce sufficient regeneration. These results indicate that other factors may still be preventing efficient cardiac regeneration after injury.

We have identified molecular pathways that are involved in the regulation of heart muscle cell proliferation, and we describe how Arid1a interacts with these pathways. Based on these observations we conclude that Arid1a is involved in suppression of heart muscle cell response to injury, and that removal of Arid1a is not sufficient to unlock the tightly regulated cell cycle in the heart.

The results of this study were presented at multiple international scientific conferences in Europe and the US. The results of this project are currently being prepared for publication in international peer-reviewed scientific journals, complying with the standards for open access. Datasets generated during this study will be made available to the scientific community through public databases upon publication of accepted manuscripts.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

We have now identified a novel mechanism that regulates heart muscle cell renewal in hearts after birth. Furthermore, we show that in the injured adult heart there is a role for Arid1a in suppression of a regenerative response. Still, other mechanisms appear to be in place that still prevent a robust pro-regenerative response. Further studies are required to unravel the roadblocks to effective cardiac regeneration after injury. These findings are important as the modulation of this pathway could contribute to the development of novel therapeutic strategies enhancing cardiac regeneration after injury.

ARID1A may suppress regeneration of heart muscle cells after injury